1. Meropenem-vaborbactam: A New Hope
June 1st, 2018
Pavithra Srinivas, PharmD, BCPS, AAHIVP
Infectious Diseases Clinical Pharmacy Specialist

2. Objectives
Recognize challenges associated with treatment of MDR Gram-negative infections
Describe the spectrum of activity and characteristics of meropenem/vaborbactam
Summarize the evidence for meropenem/vaborbactam’s place in therapy

3. Burden of Antimicrobial Resistance
Antibiotic resistance associated with over $20 billion in direct health care related costs
MDR Gram negative infections associated with significant clinical and economic burden
Increased severity of illness
Higher hospital and antibiotic costs
Increased hospital and ICU length of stay
CRE: Carbapenem Resistant Enterobacteriaceae
Biggest challenge: Limited treatment options
Kaye KS, Pogue JM. Pharmacotherapy 2015; 35(10):

4. β-lactam Resistance Porin loss/deletion β-lactamase Efflux pump
Antibiotic
Periplasmic space
Enzyme
Porin loss/deletion
β-lactamase
Efflux pump
Cytoplasm
Munoz-Price L, Weinstein RA. N Engl J Med. 2008; 358 :

5. Types of β-lactamases Ambler class Active site Type Examples
β-lactam antimicrobial(s) affected A
Serine
Narrow spectrum
Extended-spectrum (ESBL)
Carbapenemases
TEM-1, SHV-1
CTX-M
KPC
Penicillins
Cephalosporins, BL-BLIC
Carbapenems B
Zinc
Metallo-β-lactamases
NDM, VIM, IMP
All β-lactams C
Cephalosporinases
AmpC
1st – 3rd generation cephalosporins D
OXA-type enzymes
OXA-23, OXA-48
Ranges from penicillins to all β-lactams
BL-BLIC: β-lactam/β-lactamase inhibitor combinations
Toussaint KA, Gallagher JC. Ann Pharmacother 2015; 49(1): 86-98

6. CRE Treatment Optimal treatment largely unknown
Monotherapy vs combination therapy
Depends on in vitro susceptibility, source and severity of infection
Limited available options:
Polymyxins, aminoglycosides, tigecycline, fosfomycin, carbapenems
Toxicity concerns and further resistance development
18-48% CRE-related mortality rate
Ceftazidime/avibactam
Morrill HJ, et al. Open Forum Infect Dis 2015; 2(2): ofv050
Rodriguez-Bano J, et al. Clin Microbiol Rev 2018; 31(2): e

7. Ceftazidime-avibactam
FDA approved in February 2015
Complicated urinary tract infections (cUTI) and acute pyelonephritis (AP)
Complicated intra-abdominal infections (cIAI), with metronidazole
Ceftazidime + novel β-lactamase inhibitor
Active against Ambler Class A (KPC), C and some Class D (OXA) enzymes
Resistance concerns
No activity against Ambler Class B (metallo-β-lactamase) enzymes
Emergence of resistance during therapy, via mutations in the blaKPC-3 gene
Reported in 10-30% of cases
Rodriguez-Bano J, et al. Clin Microbiol Rev 2018; 31(2): e
Shields RK, et al. Open Forum Infect Dis 2017; 4: ofx101
Shields RK, et al. Clin Infect Dis 2016; 63(12):

8. Vaborbactam Cyclic boronic acid based β-lactamase inhibitor
Potent activity against Ambler Class A & C β-lactamases
KPC, CTX-M, AmpC, TEM, SHV
Does NOT enhance susceptibility for:
Pseudomonas aeruginosa
Acinetobacter spp.
Organisms exhibiting Ambler Class B or D β-lactamases
Lomovskaya O, et al. Antimicrob Agents Chemother 2017; 61(11): e
Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017

9. Vaborbactam vs Avibactam
Partner β-lactam
Meropenem
Ceftazidime
Structure
Boronic acid
Diazabicyclooctane
Active site
Serine
β-lactamase inhibition (Ambler Class)
TEM, SHV, CTX-M, KPC (A)
+++
Metallo-β-lactamases (B) -
AmpC (C) ++
OXA-type carbapenemases (D) +
Lomovskaya O, et al. Antimicrob Agents Chemother 2017; 61(11): e
Wong D, et al. Drugs 2017; 77:

10. Meropenem-vaborbactam (Vabomere™)
FDA approval: October 2017
Treatment of cUTI and pyelonephritis caused by susceptible pathogens
Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex
Organism
MIC (meropenem/vaborbactam) S I R
Enterobacteriaceae
≤ 4/8
8/8
≥ 16/8
MIC: Minimum inhibitory concentration (mcg/mL)
Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017

11. Pharmacokinetics Meropenem Vaborbactam Half-life 1.22 ± 0.3 hours
Volume of distribution
20.2 L
18.6 L
Intrapulmonary penetration rate
63%
53%
Excretion
40-60% in urine
75-95% in urine
Pharmacodynamic parameter
%T > MIC
AUC24/MIC
Meropenem and vaborbactam achieve a similar time course of concentration in plasma and ELF
Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017

12. Dosing Considerations
Dosing: 4 grams IV every 8 hours
Meropenem 2 grams + vaborbactam 2 grams (1:1 ratio)
3-hour IV infusion
eGFR* (ml/min/1.73m2)
Recommended dose
(as total of meropenem and vaborbactam)
≥ 50
4 grams every 8 hours
30-49
2 grams every 8 hours
15-29
2 grams every 12 hours
< 15
1 gram every 12 hours
For reference, regarding BL/BLI combination ratio previously: PIP/TAZO (8:1 ratio), CAZ/AVI (4:1 ratio)
*Calculated using MDRD formula
Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017

13. Precautions Seizure potential CNS effects Thrombocytopenia
Risk factors: CNS disorders, bacterial meningitis, renal dysfunction
Risk of breakthrough seizures due to drug-interaction with valproic acid
CNS effects
Neuro-motor impairments including headaches, paresthesia, delirium
Thrombocytopenia
Increased risk in patients with renal dysfunction
Clostridium difficile-associated diarrhea
Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017

14. Clinical Trials
TANGO: Targeting Antibiotic Non-susceptible Gram-negative Organisms
TANGO I
TANGO II
Features
Site/Indication focused
Pathogen-focused
Patients
cUTI and acute pyelonephritis
cUTI, cIAI, HABP/VABP and/or bacteremia due to CRE
Design
Randomized 1:1
Double-blind
Randomized 2:1
Open-label
Comparator
Piperacillin-tazobactam
“Best Available Therapy”
Status
Completed
Loutit J, et al. Oral Abstract. ID Week, New Orleans, October 2016

15. TANGO I - Study Design
Meropenem-vaborbactam (M-V) vs Piperacillin/tazobactam (P-T) for cUTI and acute pyelonephritis
Design
Randomized, double blind, double dummy, active controlled, non-inferiority
Intervention
M-V 2-2 g IV q8h over 3 hours
Optional switch to PO levofloxacin
Total duration 10 days
P-T 4.5 g IV q8h over 30 minutes
Population
Inclusion: Adults with cUTI or acute pyelonephritis and ≥ 2 signs/symptoms
Require at least 5 days of IV antibiotics
Exclusion: CrCl <30 mL/min or receipt of antibiotic within 48 hours
Endpoints
Clinical cure or improvement and microbiological eradication composite at end of therapy
Non-inferiority margin set at -15%
Demographics
N = 272
N = 273
Mean age: 53 years
Mean age: 52.6 years
59.2% acute pyelonephritis
59% acute pyelonephritis
40.8% cUTI
41% cUTI
28.3% met SIRS
33% met SIRS
46% with E.coli at baseline
43% with E.coli at baseline
FDA endpoint: clinical cure or improvement and microbiological eradication at EOT
EMA endpoing: Microbiological eradication at TOC visit (7d post therapy)
Loutit J, et al. Oral Abstract. ID Week, New Orleans, October 2016

16. TANGO I - Results 4.5, 95% CI [0.7, 9.1] 9.0, 95% CI [-0.9, 18.7]
Among patients with cUTI, including AP, and growth of a baseline pathogen, M-V vs P-T resulted in a composite outcome of complete resolution or improvement of symptoms along with microbial eradication that met the noninferiority criterion.
Kaye KS, et al. JAMA 2018; 319(8):
Loutit J, et al. Oral Abstract. ID Week, New Orleans, October 2016

17. TANGO I - Adverse Effects
Meropenem-vaborbactam (N = 272)
Piperacillin-tazobactam (N = 273)
Treatment emergent adverse events
39%
35.5%
Drug-related adverse events
15.1%
12.8%
Adverse effects occurring in > 1% of patients
Headache
8.8%
4.4%
Infusion-site reactions
0.7%
Diarrhea
3.3%
Hypersensitivity
1.8%
Nausea
1.5%
Other ADRs: hypersensitivity, nausea, AST/ALT increase, pyrexia, hypokalemia
Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017
Loutit J, et al. Oral Abstract. ID Week, New Orleans, October 2016

18. TANGO I - Summary Meropenem-vaborbactam
Non-inferior and statistically superior to piperacillin-tazobactam for overall success at end of therapy for cUTI/AP
Adverse effect profile similar to piperacillin-tazobactam

19. 72 patients enrolled, 43 (59.7%) with baseline CRE
TANGO II - Study Design
Meropenem-vaborbactam (M-V) vs Best Available Therapy (BAT) for CRE Infections
Design
Randomized (2:1), open-label
Intervention
M-V 2-2 g IV q8h over 3 hours
Total duration 7-14 days
BAT
Population
Inclusion: Adults with confirmed cUTI/AP, HABP/VABP, bacteremia, or cIAI due to a known or suspected CRE pathogen, requiring at least 7 days of IV therapy
Exclusion: Infections due to MBL or OXA-β-lactamase producing organisms, or receipt of >24 h of potentially effective antimicrobial therapy
Endpoints
Clinical cure and microbiological eradication (cUTI/AP, cIAI)
28-day all cause mortality (HABP/VABP, bacteremia)
Baseline Characteristics
72 patients enrolled, 43 (59.7%) with baseline CRE
N = 28 with baseline CRE
N = 15 with baseline CRE
Mean age: 64 years
Mean age: 60 years
89% K. pnuemoniae
80% K. pneumoniae
Kaye KS, et al. Poster #1862. ID Week, San Diego, October 2017
Wunderink R, et al. Poster #1867. ID Week, San Diego, October 2017

20. TANGO II - Best Available Therapy
Monotherapy: 4/15 (26.7%)
Aminoglycoside (1), carbapenem (1), ceftazidime-avibactam (1), polymyxin (1)
Dual Therapy: 7/15 (46.7%)
Carbapenem + aminoglycoside (1)
Carbapenem + polymyxin (1)
Carbapenem + tigecycline (2)
Polymyxin + aminoglycoside (3)
Triple Therapy: 1/15 (6.7%)
Carbapenem + polymyxin + tigecycline (1)
≥ 4 Agents: 2/15 (13.3%)
Carbapenem + polymyxin + tigecycline + aminoglycoside (2)
Kaye KS, et al. Poster #1862. ID Week, San Diego, October 2017

21. TANGO II - Results 31, 95% CI [1.2, 60.7] p = 0.04
Kaye KS, et al. Poster #1862. ID Week, San Diego, October 2017

22. TANGO II - Results 41.8, 95% CI [11.1, 72.4] p = 0.008
Kaye KS, et al. Poster #1862. ID Week, San Diego, October 2017

23. TANGO II - Resistance Analysis
M-V treatment associated with lower incidence of MIC increase than C-A (4% vs 25%)
4-fold increase in M-V MIC still maintained overall susceptibility (i.e. MIC ≤ 4)
Increased expression of efflux pump
C-A MIC increase conferred full resistance
Mutations in blaKPC2 gene, porin channel deletion, efflux pump overexpression
C-A resistant isolate maintained susceptibility to M-V
M-V MIC increase in 1/25 patients (4%), C-A MIC increase in 1/4 patients (25%)
M-V: meropenem-vaborbactam
C-A: ceftazidime-avibactam
Lomovskaya O, et al. Poster #1874. ID Week, San Diego, October 2017

24. On the horizon Pediatrics Pneumonia – HAP/VAP (TANGO III)
Phase I, dose finding, PK, safety and tolerability study
Recruiting, estimated completion in Sept 2019
Pneumonia – HAP/VAP (TANGO III)
Phase III, double-blind, randomized study
Piperacillin/tazobactam comparator arm
Not yet recruiting

25. Summary
Carbapenem-resistant Enterobacteriaceae (CRE) present a therapeutic challenge due to the limited availability of active antimicrobial agents
Meropenem/vaborbactam is a new agent comprising a carbapenem and a novel β-lactamase inhibitor
Meropenem-vaborbactam has demonstrated potent activity against KPC-producing CREs
Concerns for developing resistance underscore the importance of judicious use of these new antimicrobials